Tranexamic acid formulations with reduced adverse effects

ABSTRACT

Tranexamic acid formulated in an oral dosage form with at least one agent that decreases tranexamic acid release in the stomach. Such formulations minimize nausea, vomiting, and other adverse gastric effects that may accompany tranexamic acid therapy, for example, to treat heavy menstrual bleeding. One embodiment is an extended release formulation with waxes, polymers, etc. that prevent a bolus release of tranexamic acid in the stomach. An alternative embodiment is a delayed release formulation with polymers that prevent release of tranexamic acid in the acid environment of the stomach and delay its release until the formulation reaches the less acid environment of the intestines. Such formulations enhance patient compliance with therapy because adverse effects of tranexamic acid therapy are reduced.

FIELD OF THE INVENTION

The invention is directed to therapeutic oral tranexamic acidformulations that minimize or eliminate undesirable side effects.

BACKGROUND

Tranexamic acid (trans-4-(aminomethyl) cyclohexanecarboxylic acid,Cyklokapron® (Pfizer) is an antifibrinolytic agent. That is, it helps toprevent lysis or dissolution of a fibrin clot which forms in the normalphysiologic process of hemostasis. Its mechanism of action is as acompetitive inhibitor of plasminogen activation, and as a noncompetitiveinhibitor of plasmin; both plasminogen and plasmin are activators offibrinolyis and active clot-lysing agents. Tranexamic acid thus helps tostabilize fibrin clots, which in turn maintains coagulation and helps tocontrol bleeding.

Tranexamic acid is used to control excess bleeding, for example, excessbleeding that occurs during dental procedures in hemophiliacs and forheavy bleeding during menstruation (menorrhagia). Women suffering frommenorrhagia are typically treated orally with 500 mg tranexamic acidtablets administered three of four times daily with a total daily doseranging from 3 grams/day (two tablets every eight hours) to 6 grams/day(three tablets every six hours). However, this treatment may causeadverse gastrointestinal reactions, including nausea, vomiting,diarrhea, and cramping, etc. These gastrointestinal side effects are dueto the quantity of tranexamic acid introduced into the stomach with eachdose, as well as the large quantity of excipients used in tabletformulation that are introduced into the stomach. Such side effects, inaddition to the cramping, bloating, pain, and other symptoms that mayaccompany menses, are undesirable, and a formulation of tranexamic acidis needed which will reduce or eliminate these side effects.

SUMMARY OF THE INVENTION

Formulations of tranexamic acid which minimize or eliminate theundesirable gastrointestinal side effects in patients on oral tranexamicacid therapy, e.g. women treated for menorrhagia (heavy menstrualbleeding), by modifying the release characteristics of tranexamic acidare disclosed. One embodiment is an extended release formulation, alsotermed a controlled release formulation, formulated so that the releaseof tranexamic acid from the dosage form occurs in an extended orcontrolled fashion to prevent a bolus of tranexamic acid beingintroduced into the stomach and available for dissolution in the gastriccontents. An alternative embodiment is a delayed release formulation.Delayed release dosage forms are formulated to minimize or prevent thedissolution of the drug in the stomach. The release of tranexamic acidis delayed until the dosage form exits the stomach and reaches the smallintestine. Both extended release dosage forms and delayed release dosageforms are termed modified release dosage forms. Such modified releaseformulations reduce the concentration of tranexamic acid dissolved inthe stomach contents. The beneficial effect of this reduced tranexamicacid concentration is to lower the amount of tranexamic acid in thegastric contents so that there are fewer gastric adverse effects withtranexamic acid therapy. This reduction in gastric adverse effectsresults in improved patient compliance with therapy, because patientswill not intentionally miss taking a dose to avoid these adverse sideeffects. Physicians will also be more likely to initiate and maintaintranexamic acid treatment for their patients because of the reducedpatient complaints.

These and other advantages will be apparent in light of the followingdetailed description and examples.

DETAILED DESCRIPTION

The present invention is a modified release tranexamic acid tablet fororal administration. The tablet contains at least one excipient (definedherein as any substance other than the active, i.e., tranexamic acid)which minimizes or eliminates the adverse gastrointestinal side effectsin patients, for example, women dosed with oral tranexamic acid fortreatment of menorrhagia.

A modified release product is defined by the United States Pharmacopeia(USP) as including delayed release products and extended-(controlled)release products. One embodiment is an extended release formulation,also called a sustained release formulation or a controlled releaseformulation. Extended, controlled, or sustained release formulationsdecrease the concentration of tranexamic acid and excipients dissolvedin the stomach fluids after dosing by controllably releasing tranexamicacid over a period of time, as opposed to immediate release formulationswhich release the entire dose of tranexamic acid all at once. Inimmediate release formulations the entire dose and the solublecomponents in the dosage form dissolve in gastric fluid and present ahigh concentration of solutes for absorption.

Another embodiment is a delayed release formulation. The definition of adelayed release dosage form used herein is that from the USP, Chapter1151 Pharmaceutical Dosage Forms—Tablets. The tablet contains one ormore coatings, intended to delay the release of tranexamic acid untilthe tablet has passed through the stomach (enteric coatings). A delayedrelease tablet is a dosage form that releases tranexamic acid at a timelater than immediately after administration, that is, it exhibits a lagtime in quantifiable plasma tranexamic concentrations. One or morecoating(s) delays the release of tranexamic acid until the dosage formhas passed through the acidic medium of the stomach.

Delayed release formulations minimize or prevent release of tranexamicacid in the stomach and delay its release until the dosage form hasemptied from the stomach into the small intestine. Delayed releaseformulations include enteric-coated tablets, enteric-coated capsules,enteric-coated granules, and enteric-coated spheres (commonly referredto as “tiny little time pills” or multiparticulate dosage forms).

The enteric coating is stable under the acidic conditions in the stomachand releases tranexamic acid only in the less acidic or substantiallyneutral medium of the intestine, (e.g., at pH about 5.5 to about 7.5).It disintegrates, erodes, or dissolves, releasing tranexamic acid onlywhen it encounters the higher pH of the intestine. Enteric-coatedformulations substantially prevent dissolution of tranexamic acid in therelatively lower pH of the stomach. Both extended release and delayedrelease formulations are modified-release forms that thus minimize orprevent gastrointestinal reactions and side effects that occur when adose of tranexamic acid is ingested and immediately reaches the stomach.

As used herein, the terms extended release formulations, controlledrelease formulations, or sustained release formulations are used todescribe drug product formulations designed to release tranexamic acidover a prolonged period of time. The definition of an extended releasetablet used herein is that from the USP, Chapter 1151, as previouslycited. The tablet is formulated in such a manner as to make tranexamicacid available over an extended period of time following ingestion.Expressions such as “prolonged action”, “repeat-action”, and “sustainedrelease” also describe such a dosage form. Extended release dosage formstypically allow reduced dosing frequency as compared to when tranexamicacid is present in an immediate release dosage from. These extendedrelease dosage forms may also reduce fluctuations in plasma tranexamicacid concentrations. Extended release dosage forms may be prepared as atablet, capsule, granule, pellet or suspension, and may be packaged intocapsules, sachets, etc. They may be prepared by any formulationtechnique where release of the active substance (tranexamic acid) fromthe dosage form is modified to occur at a slower rate than that from animmediate release product. In these formulations, tranexamic acidrelease occurs both in the stomach and intestine, but at a slower rateso that a bolus of dissolved drug does not reach the lining of thestomach or intestine and cause adverse effects, or adverse effects occurwith a lower intensity or frequency because of the lower concentrationof tranexamic acid. Hence, adverse effects are reduced, minimized oreliminated.

Methods of preparing extended release formulations are known to oneskilled in the art and are found in Modified Release Drug DeliveryTechnology, Rathbone, Hadgraft, and Roberts, Eds., Drugs and thePharmaceutical Sciences, Vol. 126, Marcel Dekker Inc, New York, 2003;Modern Pharmaceutics, Third Edition, Banker and Rhodes, Eds., Drugs andthe Pharmaceutical Sciences, Vol. 72, Marcel Dekker Inc., New York,1996; Sustained and Controlled Release Drug Delivery Systems, Robinson,Ed., Drugs and the Pharmaceutical Sciences, Vol. 6, Marcel Dekker Inc.,NY 1978; Sustained Release Medications, Chemical Technology Review No.177, Johnson, Ed., Noyes Data Corporation 1980; Controlled DrugDelivery, Fundamentals and Applications, Second Edition, Robinson andLee, Eds., Marcel Dekker Inc., New York, 1987, and as described in U.S.Pat. No. 6,548,084, which is expressly incorporated by reference hereinin its entirety. The terms extended release formulation, controlledrelease formulation, and sustained release formulation are usedinterchangeably herein, unless indicated otherwise.

An extended release form, one example of a modified release form, makestranexamic acid available over an extended period of time afteringestion. Extended release dosage forms coupled with the digestionprocess and the absorption process in the gastrointestinal tract cause areduction in the amount of tranexamic acid in solution in thegastrointestinal tract compared to dosing tranexamic acid presented as aconventional dosage form (e.g., as a solution, or as an immediaterelease dosage form). The extended release formulation may be verifiedby in vitro dissolution testing and in vivo bioequivalencedocumentation, according to Food and Drug Administration standards, e.g,as set forth at www.fda.gov, 21 CFR §314, 320, and also at USP 23 NF 18§711, 724. Briefly, in vitro dissolution is conducted on twelveindividual dosage units. Multipoint dissolution profiles are obtainedusing discriminating combinations of apparatus, agitation speed, andmedium. A surfactant may be used if justified. Sampling times areselected to define the release characteristics of the dosage form and toassure batch to batch reproducibility. Suitable equipment fordissolution testing is specified in USP 23 Apparatus 1 (rotatingbasket); Apparatus 2 (rotating paddle); Apparatus 3 (reciprocatingcylinder*), Apparatus 4 (flow-through cell*); and Apparatus 5(reciprocating disk*) (*modified testing conditions are used). Rotationspeeds of 50 rpm, 100 rpm and 150 rpm are used with baskets, and 50 rpm,75 rpm and 100 rpm are used with paddles. The temperature is 37° C.±0.5°C. The dissolution volume is 500 ml to 1000 ml. The dissolution mediumis aqueous, at various pH values. The sampling schedule is such thatadequate sampling is performed until either 80% of tranexamic acid isreleased or an asymptote is reached.

Tranexamic acid extended release tablets may be formulated to provide adose of tranexamic acid, typically 1-2 grams from one to two tablets,within about the first one to two hours after the tablet is ingested.Thus, tranexamic acid release occurs at a controlled rate over anextended period, e.g., about 60 minutes to about 120 minutes. Thecontrolled rate of tranexamic acid release over this period of time isdesigned to provide a reduced concentration of tranexamic acid in thestomach while allowing the absorption of tranexamic acid to occurthroughout the gastrointestinal tract. Absorption of tranexamic acidbegins as soon as tranexamic acid is released from the dosage form andis dissolved in the gastrointestinal fluids contacting the membraneswhich line the gastrointestinal tract. The controlled and extendedrelease of tranexamic acid from the dosage form and the absorption ofdrug by the gastrointestinal mucosa help to maintain low concentrationsof drug in the gastrointestinal fluids. The lowered concentrationsresult in lower intensity, frequency, and/or severity ofgastrointestinal adverse side effects. The extended release oftranexamic acid from the dosage form in the stomach and the upper smallintestine, the natural emptying of gastric juice containing anydissolved tranexamic acid from the stomach, and the absorption oftranexamic acid from a larger segment of the gastrointestinal tract(i.e., both the stomach and the small intestine, rather than the stomachonly or the lower portion of the small intestine if an extended releasedosage form with a longer release time was used), results in reducedlevels of dissolved tranexamic acid in the region of thegastrointestinal tract proximal or distal to the dosage form. Reducedconcentrations of tranexamic acid along the gastrointestinal tractreduces adverse gastrointestinal effects associated with oral tranexamicacid therapy.

As used herein, the term delayed release formulation indicates anyformulation technique where release of the active substance (tranexamicacid) from the dosage form is modified so that release occurs at a latertime than that from a conventional immediate release product. Oneexample of a delayed release formulation is an enteric coatedformulation. Enteric coatings on the dosage form are intended to controlthe region of the gastrointestinal tract where dissolution andsubsequent absorption of tranexamic acid from the enteric coated dosageform occurs. Enteric coatings can be prepared to substantially preventdissolution of the dosage form contents in the stomach. These coatingsfunction by incorporating materials in the enteric coating which allowthe enteric coating to remain substantially intact in the acidicenvironment of the stomach. This substantially intact enteric coatingminimizes or prevents the dissolution of tranexamic acid in stomachcontents. Enteric coatings are formulated to release the contents of thedosage form when the pH of the gastrointestinal fluid increases. Thisincrease in pH typically occurs when the dosage form passes out of thestomach into the small intestine. That is, the coating remains intact inthe relatively more acidic stomach pH (pH≦2) and disintegrates,dissolves, or is otherwise removed in the relatively less acidic pH ofthe intestine (pH≧2 about 5 for the upper regions of the small intestineand pH values from about 7 to about 8.5 in the lower regions of theintestines). Formulations can be prepared using enteric coatingsintended to release tranexamic acid at pH values of about 5.5 to about6.5 or at higher pH values that typically occur in the lower regions ofthe intestines. In those delayed release formulations intended todissolve at pH 5.5 to about 6.5 or higher, tranexamic acid releaseoccurs substantially only upon reaching the duodenum (the upper portionof the small intestine) so that substantially no tranexamic acid isreleased in the stomach, thus minimizing or eliminating adverse effects.

Tranexamic acid formulated as delayed release tablets may contain anenteric coating which disintegrates, dissolves, or erodes at neutral orslightly acidic or slightly alkaline pH, and thereby allows dissolutionof tranexamic acid upon leaving the stomach, that is, upon stomachemptying into the small intestine. The release of tranexamic acid in theintestine reduces gastrointestinal side effects associated with thelarge dose of tranexamic acid quickly released into the stomach.Patients treated with enteric coated formulations of tranexamic acid fordelayed release should be cautioned to not consume antacids while undertranexamic therapy, because antacids will change the stomach pH and thusalter the site of tablet dissolution or disintegration. Other types ofdelayed release formulations are available, and the above example is notlimiting.

A delayed release form, another example of a modified release form,makes tranexamic acid available at a time other than immediatelyfollowing oral administration. As for extended release formulations,delayed release formulations may be verified by in vitro dissolutiontesting and in vivo bioequivalence documentation according to thestandard available as previously set forth (USP 23 NF 18, §§711, 724).When the guidance refers to dissolution testing in addition toapplication/compendial release requirements, the dissolution test shouldbe performed in 0.1 N HCl for two hours (acid stage), followed bytesting in USP buffer media at a pH range between 4.5 to 7.5 (bufferstage) under standard (application/compendial) test conditions andincreased agitation speeds using the application/compendial testapparatus. For the rotating basket method (Apparatus 1) a rotation speedof 50 rpm, 100 rpm, and 150 rpm may be used, and for the rotating paddlemethod (Apparatus 2) a rotation speed of 50 rpm, 75 rpm, and 100 rpm maybe used. Multipoint dissolution profiles should be obtained during thebuffer stage of testing. Adequate sampling should be performed, e.g., at15 min, 30 min, 45 min, 60 min, 120 min (following the time from whichthe dosage form is placed in the buffer), until either 80% of the drugis released or an asymptote is reached.

Methods of preparing delayed release formulations are known to oneskilled in the art and are found in, for example, Remington'sPharmaceutical Sciences 16^(th) Edition, Mack Publishing Company 1980,Osol, Ed., and the references cited for extended release formulations.

As used herein, alleviation of adverse effects using these formulationsindicates any relief in one or more symptoms, such as decrease inincidence, severity, or duration of symptoms, and is not limited toabsence of symptoms or elimination of symptoms. Thus, treatment includesany decrease in incidence, duration, intensity, frequency, etc. ofadverse gastrointestinal symptoms including, but not limited to, nausea,bloating, cramping, vomiting, diarrhea, and constipation. Theformulations may reduce symptoms at any time during tranexamic acidtherapy, but minimized adverse effects are particularly notedimmediately or shortly after dosing, that is, within the first few hoursafter dosing. As used herein, adverse gastrointestinal effects and sideeffects are used interchangeably to indicate non-therapeutic effects(i.e., not relating to any possible beneficial effects due to tranexamicacid), ranging from unpleasant but tolerable sensations to severegastrointestinal symptoms. As used herein, the terms oral formulations,ingestable formulations, and orally administered formulations are usedinterchangeably and include any dosage forms which are ingested bymouth, including, but not limited to, tablets, pills, liquids, gelcaps,dragees, capsules, powders, granules, pellets, etc.

Delayed release formulations may be enteric coated tranexamic acidtablets or enteric coated granules. These tablets may be prepared bycoating compressed tablets with a commercial or specially formulatedenteric film coat, for example, a wax, polymer, and/or a pH-sensitivematrix that meets (USP) and Food and Drug Administration (FDA)requirements for enteric coated tablets. The enteric coating permitsdisintegration of the tranexamic acid tablets and dissolution oftranexamic acid as a result of the pH change between the stomach and theduodenum. Tablet excipients which inhibit rapid release of tranexamicacid in the stomach and which promote dissolution and release in theintestine may also be used. These include, but are not limited to,phthalic acid derivatives such as phthalic acid derivatives of vinylpolymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses,cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers,alkylcellulose acetates and partial esters thereof, and polymers andcopolymers of lower alkyl acrylic acids and lower alkyl acrylates andpartial esters thereof. Commercial preparations intended for the entericcoating of tablets, capsules, and granules are available from Degussa(Parsippany, N.J.) and Colorcon (West Point, Pa.). In one embodiment,the polymers are methacrylic acid copolymers. These are copolymers ofmethacrylic acid with neutral acrylate or methacrylate esters such asethyl acrylate or methyl methacrylate, for example, methacrylic acidcopolymer, Type C, USP (a copolymer of methacrylic acid and ethylacrylate having between 46.0% and 50.6% methacrylic acid units),commercially available from Rohm Pharma as Eudragit® L 100-55 (as apowder) or L30D-55 (as a 30% dispersion in water). In anotherembodiment, the polymers are hydroxypropyl cellulose phthalate,hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate,polyvinylacetate phthalate, polyvinylpyrrolidone phthalate, and thelike. One or more pH-dependent excipient(s) are present in amountsranging from about 1% by weight to about 20% by weight, from about 5% byweight to about 12% by weight, or in an amount of about 10% by weight.

The quantity of pH dependent excipients is sufficient to produce adelayed release formulation from which the release rate of tranexamicacid is controlled such that at a pH below about 5 the rate ofdissolution is significantly retarded. For methacrylic acid copolymer,type C, USP (Eudragit® L 100-55), a quantity of pH dependent polymercoating may be applied to tablets in the range between about 2% to about15% by weight (dry basis). In another embodiment, the range is betweenabout 3% to about 6% by weight (dry basis). The pH dependent polymer mayhave from about 1% to about 20% of the methacrylic acid carboxyl groupsneutralized. In one embodiment about 3% to about 6% of the bindermethacrylic acid carboxyl groups are neutralized. One or more pHindependent excipients may be present in amounts ranging from about 1%by weight to about 10% by weight, from about 1% by weight to about 3% byweight, or in an amount of about 2% by weight. Film-forming or viscosityenhancing agents may also be present, such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose,polyvinylpyrrolidone, neutral poly(meth)acrylate esters, and the like.

Excipients may be admixed so as to form a homogeneous mixture withtranexamic acid and the pH dependent binder. Excipients include pHindependent binders or film-forming agents such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose,polyvinylpyrrolidone, neutral poly(meth)acrylate esters (e.g., themethyl methacrylate/ethyl acrylate copolymers sold as Eudragit® (RohmPharma), starches, gelatin, sugars such as glucose, sucrose, andmannitol, silicic acid, carboxymethylcellulose, and the like, diluentssuch as lactose, mannitol, dry starch, microcrystalline cellulose andthe like, surface active agents such as polyoxyethylene sorbitan esters,sorbitan ethers, and the like, coloring agents, flavoring agents,lubricants such as talc, calcium stearate, and magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and other tableting aids.These excipients may be combined with tranexamic acid to form delayedrelease tablets.

In one embodiment of tranexamic tablets, tranexamic acid is in the rangeof about 50% by weight to about 95% or more by weight. In otherembodiments, tranexamic acid is in the range of about 70% by weight toabout 90% by weight, or about 70% by weight to about 80% by weight. ThepH dependent binder may be in the range of about 5% by weight to about40% by weight, about 5% by weight to about 25% by weight, or about 5% byweight to about 15% by weight. The remaining weight may be made up of pHindependent binders, fillers, or other excipients.

To prepare delayed release tablet formulations, the agent to control therelease of tranexamic acid may be incorporated into the tablet matrix orcoated onto the tablet surface or both. Tablet formulations preparedwith the pH dependent excipient added as a binder in the tablet matrixare formulated by granulating a blend of powders composed with the pHdependent binder. Alternatively, the pH dependent binder may be added asa powder and wet granulated by addition of a solvent to the powderblend. The powder blend is formed by combining portions of the powderedcomponents that make up the tablet. These powders are intimately mixedby dry-blending. The dry blended mixture is granulated by wet mixing ofa solution of a binding agent with the powder blend. The time for suchwet mixing may be controlled to influence the dissolution rate of theformulation. For example, the total powder mix time, that is, the timeduring which the powder is granulated, may range from about 1 min toabout 10 min, or from about 2 min to about 5 min. Following granulation,the particles are removed from the granulator and placed in a fluid beddryer, a vacuum dryer, a microwave dryer, or a tray dryer for drying.Drying conditions are sufficient to remove unwanted granulating solvent,typically water, or to reduce the amount of granulating solvent to anacceptable level. Drying conditions in a fluid bed dryer or tray dryerare typically about 60° C. The granulate is dried, screened, mixed withadditional excipients such as disintegrating agents, flow agents, orcompression aids and lubricants such as talc, stearic acid, or magnesiumstearate, and compressed into tablets.

The tablet that contains a delayed release agent within the tabletmatrix may be coated with an optional film-forming agent. This appliedfilm may aid in identification, mask an unpleasant taste, allow desiredcolors and surface appearance, provide enhanced elegance, aid inswallowing, aid in enteric coating, etc. The amount of film-formingagent may be in the range of about 2% tablet weight to about 4% tabletweight. Suitable film-forming agents are known to one skilled in the artand include hydroxypropyl cellulose, cellulose ester, cellulose ether,one or more acrylic polymer(s), hydroxypropyl methylcellulose, cationicmethacrylate copolymers (diethylaminoethyl)methacrylate/methyl-butyl-methacrylate copolymers such as Eudragit E®(Rohm Pharma) and the like, The film-forming agents may optionallycontain colorants, plasticizers, fillers, etc. including, but notlimited to, propylene glycol, sorbitan monooleate, sorbic acid, titaniumdioxide, and one or more pharmaceutically acceptable dye(s).

In one embodiment, tranexamic acid tablets are coated with an entericfilm coat. Tranexamic acid tablets are formulated by dry blending,rotary compacting, or wet granulating powders composed of tranexamicacid and tablet excipients. These powders are compressed into animmediate release tablet. Coating this immediate release tablet with anenteric coating renders this tranexamic acid tablet as a delayed releasetablet.

Extended release formulations of tranexamic acid include tablets,pellets, granules, capsules, or other oral dosage forms prepared in sucha way to release tranexamic acid in a controlled manner.

Extended release tranexamic acid tablets are prepared by adding agel-forming or hydratable polymer to a tranexamic tablet composition.Suitable gel-forming or hydratable polymers include, but are not limitedto, hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, polyvinyl alcohol, etc. This provides acompressed tablet that may or may not be film-coated. The tabletreleases tranexamic acid by diffusion of tranexamic acid through thetablet matrix, or by erosion of the tablet matrix, or by a combinationof diffusion from and erosion of the tablet matrix. Alternatively,water-swellable polymers may be used to form the tablet matrix. Tabletsformed with water swellable polymers release tranexamic acid bydiffusion of tranexamic acid through the tablet matrix, or by erosion ofthe tablet matrix, or by a combination of diffusion from and erosion ofthe tablet matrix. One or more water-soluble hydrophilic polymer(s) mayalso be used. These include polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose, now referred to as hypromellose(e.g., Methocel™, Dow Chemical Company), methyl cellulose, vinylacetate/crotonic acid copolymers, methacrylic acid copolymers, maleicanhydride/methyl vinyl ether copolymers, derivatives thereof andmixtures thereof. In various embodiments, the polymer is hydroxypropylcellulose or hydroxypropylmethylcellulose. The polymer may behydroxypropyl-methyl cellulose with a viscosity ranging from about 50cps to about 200 cps. The polymer may be hydroxypropylmethylcellulosewith a viscosity of 100 cps, commercially available as Methocel™ K 100LV (Dow Chemical Company). The amount of polymer in the composition maybe in the range of about 5% by weight to about 50% by weight of thecomposition. In various embodiments, the polymer is in the range ofabout 10% by weight to about 35% by weight of the composition, or about10% by weight to about 30% by weight of the composition.

The tablet matrix may also contain soluble and insoluble components toaid in the formulation and/or the extended release rate of tranexamicacid. The release process may be adjusted by varying the type, amount,and the ratio of the tablet ingredients to produce the desireddissolution profile, as known to one skilled in the art. A coating maybe a partially neutralized pH-dependent binder that controls the rate oftranexamic acid dissolution in aqueous media across the range of pH inthe stomach, which has a pH of about 2, and the intestine, which has apH of about 5.5. One or more pH dependent binders are used to controlthe dissolution profile so that tranexamic acid is released slowly andcontinuously as the formulation passes through the stomach andgastrointestinal tract.

In one embodiment, compressed extended release tablets are formulated tocomply with USP criteria and to be of such a size and shape to be easyto swallow. The size of the tablet will depend upon the dose oftranexamic acid that is needed to provide adequate therapy and theparticular formulation and excipients that are selected to provide thephysical properties necessary for tableting and for extended release. Invarious embodiments, a compressed extended release tablet contains fromabout 500 mg to about 1 gram of tranexamic acid, or from about 600 mg toabout 750 mg of tranexamic acid. The daily dose of tranexamic acid maybe achieved by taking one or two tablets at each dosing time.

In one embodiment, the dose of tranexamic acid per tablet is in therange of about 500 mg to about 1000 mg for tablets and from about 500 mgto about 1500 mg for a sachet filled with granules. In anotherembodiment, the dose of tranexamic acid is in the range of about 3grams/day to about 6 grams/day in three or four divided doses. As anexample, a total daily dose of 3 grams tranexamic acid may be dividedinto three doses of one tablet each with each tablet containing 1 gramtranexamic acid, or may be divided into four doses of one tablet eachwith each tablet containing 0.775 gram tranexamic acid. As anotherexample, a total daily dose of 4 gram tranexamic acid may be dividedinto three doses of two tablets at each dose with each tablet containing0.666 gram tranexamic acid, or may be divided into four doses of onetablet each with each tablet containing 1 gram tranexamic acid. Asanother example, a total daily dose of 5 gram tranexamic acid may bedivided into three doses of one tablet each with each tablet containing0.833 gram tranexamic acid, or may be divided into four doses of twotablets each with each tablet containing 0.625 gram tranexamic acid. Asanother example, a total daily dose of 6 gram tranexamic acid may bedivided into three doses of two tablets each with each tablet containing1 gram tranexamic acid, or may be divided into four doses of two tabletseach with each tablet containing 0.75 gram tranexamic acid. For ease ofswallowing, the dose of tranexamic acid taken at each dosing time may bedelivered by taking multiple tablets. For example, the 4 gram daily dosemay be delivered by taking two 666.67 mg tablets three times a day ortwo 500 mg tablets four times a day. Similarly, the 3 gram daily dosemay be achieved by taking two 550 mg tablets three times a day or two375 mg tablets four times a day. Alternatively, for ease of reference, adose of 600 mg, 650 mg, or 700 mg of tranexamic acid per tablet may beused. Alternatively, each dose may be delivered by taking granulescontaining the prescribed amount of tranexamic acid presented in aconvenient unit dose package. Such examples are not limiting and otherdoses within these ranges will be appreciated by those skilled in theart.

Alternatively, extended release or delayed release tranexamic acidformulations may be administered by pellets or granules in a sachet.Extended release tranexamic acid pellets or granules may be prepared byusing excipients to control the release of tranexamic acid from thegranule or pellet matrix. Extended release preparations may also beformulated using coatings to control the release of tranexamic acid fromthe granule or pellet. Delayed release formulations may be prepared byincorporating excipients to control the release of tranexamic acid inthe matrix of the granule or pellet, or as coating materials on thesurface of the granule or pellet. U.S. Pat. No. 6,433,215, which isexpressly incorporated by reference herein in its entirety, discloses amethod of building layers of drug and binder on sugar spheres andcoating them with a membrane to form a film coating. Such a coating maybe used for either an extended release formulation or a delayed releaseformulation, and/or for pharmaceutical elegance. U.S. Pat. Nos.5,650,174; 5,229,135; and 5,242,337, each of which is expresslyincorporated by reference herein in its entirety, disclose variations onfabricating a pellet or nonpareil dosage form. Spheres are filled intopackets, termed sachets, which are filled by weight to contain theprescribed dose of drug. Multiparticulates may be coated with anextended release coating or a delayed release coating, as disclosed inU.S. Pat. No. 6,066,339, which is expressly incorporated by referenceherein in its entirety. Coated multiparticulates may be packaged incapsules or sachets. The formulation of granules or pellets for extendedor delayed release is described in Multiparticulate Oral Drug Delivery,Ghebre-Sellassie, Ed. in Drugs and the Pharmaceutical Sciences, Vol. 65,Marcel Dekker Inc., NY, 1994 and in the relevant parts of the referencesfor extended release formulations and delayed release formulationspreviously cited and the relevant portions incorporated herein byreference.

The inventive tranexamic acid formulations may be used for additionalindications other than menorrhagia.

The invention will be further appreciated with respect to the followingexamples.

EXAMPLE 1

A sustained release formulation includes pH-dependent and -independentbinders. Tranexamic acid (5333 g) is combined with methacrylic acidcopolymer, Type C (Eudragit® L 100-55 (Rohm Pharma) (200 g),microcrystalline cellulose (Avicel®) (142 g), and polyvinyl pyrrolidonepowders (20 g) and intimately mixed in a Fielder PMA 65mixer-granulator. The mixture is granulated with a solution of sodiumhydroxide (8 g) in water, and a 30% aqueous dispersion of methylmethacrylate/ethyl acrylate copolymer (Eudragit® NE 30 D (Rohm Pharma)(300 g) is added to the wet mass. The resulting granulate is dried in anAeromatic Strea-5 fluid bed drier, screened, and then mixed withcroscarmellose sodium (10 g) and magnesium stearate (10 g). The mixtureis compressed into tablets with a Manesty B tablet press to achieve adose of 700 mg tranexamic acid per tablet.

EXAMPLE 2

A sustained release formulation is prepared according to Example 1except that Eudragit® L 100-55 is reduced to 100 g, and Eudragit® NE 30D is replaced by a 40% aqueous dispersion of a methyl methacrylate/ethylacrylate copolymer (Eudragit® NE 40 D (Rohm Pharma) 200 g).

EXAMPLE 3

A sustained release formulation is prepared by blending tranexamic acid700 mg/tablet with microcrystalline cellulose and polyvinylpyrrolidineK25, granulating with water, drying, and blending with croscarmellosesodium and magnesium stearate. The blend is compressed into tablets andcoated with an enteric coating.

EXAMPLE 4

An extended release composition is prepared by mixing tranexamic acid(3000 g) and from about 100 g to about 300 g Methocel™ K 100 LV (DowChemical Company). The mixture is dry blended, and then is granulatedusing water until proper granulation is obtained, as known to oneskilled in the art. Wet granules are dried in a fluid bed dryer, sifted,and ground to appropriate size. Lubricating and flow agents are mixedwith the dried granulation to obtain a final formulation which iscompressed into tablets containing 650 mg of tranexamic acid per tablet.

EXAMPLE 5

Methocel™ K 100 LV (Dow Chemical Company) is loaded into a mixer and dryblended with tranexamic acid. The mixture is granulated using wateruntil proper granulation is obtained, as known to one skilled in theart. The granulation is then dried, sifted, and ground to appropriatesize.

Talc and magnesium stearate are screened and blended with drygranulation. The granulation is loaded into a hopper and compressed intotablets. Tablets are then coated with an aqueous film coating.

In the following formulations, 650 mg tranexamic acid tablets arecompressed from the granulation with water added up to the desiredquantity (qs).

Formulation one contains 50 mg/tablet Methocel™ K 100 LV Premium CRGrade (Dow Chemical Company), 50 mg/tablet lactose monohydrate, 25mg/tablet USP talc, and 8 mg/tablet magnesium stearate.

Formulation two contains 75 mg/tablet Methocel™ K 100 LV Premium CRGrade (Dow Chemical Company), 50 mg/tablet lactose monohydrate, 25mg/tablet USP talc, and 10 mg/tablet magnesium stearate.

Formulation three contains 100 mg/tablet Methocel™ K 100 LV Premium CRGrade (Dow Chemical Company), 50 mg/tablet lactose monohydrate, 30mg/tablet USP talc, and 10 mg/tablet magnesium stearate.

Other variations or embodiments of the invention will also be apparentto one of ordinary skill in the art from the above descriptions andexamples. Thus, the forgoing embodiments are not to be construed aslimiting the scope of this invention.

1. A composition comprising a pharmaceutically acceptable ingestablesolid formulation comprising tranexamic acid and at least one agent thatmodifies the release of tranexamic acid from the formulation in thegastrointestinal tract.
 2. The composition of claim 1 wherein the agentretards the rate of tranexamic acid release from the composition in thestomach and intestine.
 3. The composition of claim 1 wherein the agentsubstantially prevents tranexamic acid release in the stomach.
 4. Thecomposition of claim 1 wherein the agent substantially prevents releaseof tranexamic acid at a pH<5.5.
 5. The composition of claim 1 whereinthe agent comprises at least one of a wax, a polymer, or a time-releasedmatrix.
 6. The composition of claim 1 wherein an amount of tranexamicacid is in the range between about 375 mg to about 1 gram.
 7. Acomposition comprising tranexamic acid in a pharmaceutically acceptablemodified release ingestable formulation.
 8. The composition of claim 7in a delayed release tablet.
 9. The composition of claim 7 in anextended release tablet.
 10. The composition of claim 7 wherein theformulation is chosen from at least one of a tablet, a capsule, agranule, a powder, a pellet, a dragee, a troche, a non-pareil, a sachet,and a pill.
 11. A composition comprising tranexamic acid in aningestable solid pharmaceutically acceptable formulation with at leastone agent in an amount sufficient to provide extended release oftranexamic acid from the composition.
 12. The composition of claim 11wherein the at least one agent reduces the rate of tranexamic releasefrom the composition.
 13. The composition of claim 11 wherein the rateis substantially uniformly reduced.
 14. The composition of claim 11wherein the agent is selected from at least one of gel-forming polymers,hydratable polymers, water soluble polymers or water swellable polymers.15. The composition of claim 11 wherein the polymers are selected fromat least one of hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone,hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose,vinyl acetate/crotonic acid copolymers, methacrylic acid copolymers,maleic anhydride/methyl vinyl ether copolymers, derivatives thereof, andmixtures thereof.
 16. The composition of claim 11 wherein a totalconcentration of the polymer is in the range of about 5% by weight toabout 50% by weight of the composition.
 17. The composition of claim 11wherein a total concentration of the polymer is in the range of about10% by weight to about 35% by weight of the composition.
 18. Thecomposition of claim 11 wherein a total concentration of the polymer isin the range of about 10% by weight to about 30% by weight of thecomposition.
 19. The composition of claim 11 wherein the polymer ishydroxypropylmethylcellulose.
 20. A composition comprising tranexamicacid in an ingestable solid pharmaceutically acceptable formulation withat least one agent sufficient to delay the release of tranexamic acidfrom the composition until encountering a pH>about 5.5.
 21. Thecomposition of claim 20 wherein the agent is at least one of phthalicacid derivatives of vinyl polymers, phthalic acid derivatives of vinylcopolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates,hydroxyalkylcellulose acetates, cellulose ethers, alkylcelluloseacetates, and partial esters thereof, and polymers and copolymers oflower alkyl acrylic acids and lower alkyl acrylates, and partial estersthereof.
 22. The composition of claim 20 wherein a total concentrationof the at least one agent is in the range of about 1% by weight to about20% by weight of the composition. 23 The composition of claim 20 whereina total concentration of the at least one agent is in the range of about5% by weight to about 12% by weight of the composition.
 24. Thecomposition of claim 20 wherein a total concentration of the at leastone agent is about 10% by weight of the composition.
 25. A therapeuticmethod comprising providing to a patient in need of tranexamic acidtherapy an ingestable solid pharmaceutically acceptable formulationcomprising a therapeutic dose of tranexamic acid and at least oneexcipient wherein the excipient retards tranexamic release in thestomach and substantially releases tranexamic acid in the smallintestine thereby reducing the concentration of tranexamic acid in thestomach during therapy.
 26. The method of claim 25 further reducingadverse gastrointestinal side effects of therapy.
 27. The method ofclaim 25 wherein the at least one excipient controls release oftranexamic acid in the stomach.
 28. The method of claim 25 wherein theat least one excipient retards release of tranexamic acid in thestomach.
 29. The method of claim 25 wherein the therapeutic dose is inthe range of about 375 mg tranexamic acid to about 1 gram tranexamicacid per dose.
 30. The method of claim 25 wherein the dose isadministered either three times a day or four times a day.
 31. Themethod of claim 30 wherein the dose is at least two solid tablets or onesachet containing granules.
 32. A therapeutic method comprisingproviding tranexamic acid therapy to a patient in need thereof in apharmaceutically acceptable oral formulation comprising at least oneexcipient sufficient to result in a decreased stomach concentration oftranexamic acid after oral ingestion thereby decreasing at least onegastrointestinal adverse effect of said therapy.
 33. The method of claim32 decreasing a gastrointestinal adverse effect selected from the groupconsisting of nausea, vomiting, diarrhea, constipation, cramping,bloating, and combinations thereof.
 34. The method of claim 32 providedto a patient having menorrhagia.
 35. A method of reducinggastrointestinal adverse side effects comprising administering aneffective amount of an extended release pharmaceutical compositioncomprising tranexamic acid and at least one agent that controls releaseof tranexamic acid from the composition in the gastrointestinal tract.36. A method of reducing gastrointestinal adverse side effectscomprising administering an effective amount of a composition comprisingtranexamic acid in an oral administrable formulation selected from thegroup consisting of extended release, delayed release, and combinationsthereof, wherein upon oral administration tranexamic acid issubstantially released in the small intestine.
 37. A method of reducinggastrointestinal adverse side effects comprising directing oraladministration of an effective amount of a delayed releasepharmaceutical composition comprising tranexamic acid and at least oneagent that delays release of tranexamic acid from the composition untilthe small intestine.